Process for the manufacture of alpha-beta-unsaturated ketones of the cyclopentanopolyhydrophenanthrene series



Patented Oct. 1941 UNITED STATES PATENT OFFICE PROCESS FOR THE MANUFACTURE OF a-fi-UNSATURATED KETONES OF THE CYCLOPENTANOPOLYHYDBOPHE- NANTHBENE SEBJE Karl Miescher, Riehen, and Albert Wettstein,

Basel, Switzerland, assilnors, by meme aasignments, to Ciba Pharmaceutical Products, Incorporated, Summit, N. 1., a corporation of New Jersey No Drawing. Application June 5. 1936, Serial No. 83,794. In Switzerland June 18, 1935 11 Claims.

elimination of hydrogen halide there are formed the corresponding compounds of the A .--aetiocholenone or A -aetio-allo-cholenone series.

For instance the A -androstene-dione of the Formula 1115 obtained from aetio-cholane-dione of the Formula I.

OH: CH:

. O J i/\/ OH: OH:

CH: CH:

III

when starting from aetio-allo-cholane-dione, the A -androstene-dione of the Formula 111 is obtained in analogous manner.

zen-497.3)

aetio-cholane-ol-(l'!) -one-(3), as well as their derivativeasuch as esters or ethers, may be converted in like manner into A or A -androstene-ol-(l'1)-one-(3) or their derivatives.

The new compounds have powerful effects, partly on the comb of capons or on the seminal vesicle, and partly in the oestrus test on the rat. They are. intended for therapeutic use.

The following examples illustrate the invention:

Example I 2.88 grams of androstane-dione of the formula CH: CH;

of melting point 132 C. are dissolved in 40 cc. of glacial acetic acid and there is added, by drops, to the solution a solution of 1.6 grams of bromine in 10 cc'. of glacial acetic acid. Rapid decolorization occurs. The product is precipitated by addition of water and purified by recrystallization from alcohol or dilute acetone; it is thus obtained in the form of splendid needles of melting point 216' C. For the purpose of eliminating hydrogen bromide this 2-bromo-androstane-dione- (3,17) is heated to boiling in cc. of dry quinoline for 5 hours. After dilution with water the quinoline is neutralized with dilute sulfuric acid and the androstene-dione which is precipitated is extracted by ether. The ethereal solution is washed with dilute sodium carbonate solution and water. The ethereal solution is then dried over sodium sulfate and evaporated. By recrystallization ofthe residue from hexane pure A androstene-dione-(3,17) of the formula CH: CH:

of melting point 142 C. is obtained.

The elimination of hydrogen halide may also be effected by heating with alkali or alkaline earth acetates in glacial acetic acid solution in- Androstane-ol-(l7) '-one-(3), its isomeride, the stead of with qulnoline. Instead of alkali ace- Example 2 3.32 grams of androstane-ol-(17)-one-(3)- acetate of the formula CH: OH: H

i o.c 0. CH|

obtained as described in French Patent No. 815,896 aredissolved in 50 cc. of glacial acetic acid and, after addition of a few drops of a solution of hydrogen bromide in glacial acetic acid, the solution is gradually mixed with one of 1.6 grams of bromine in cc. of glacial acetic acid. Decolorization occurs at once. The product is precipitated by addition of water and then recrystallized from dilute acetone; it is thus obtained in the form'of splendid needles. For the purpose of. eliminating hydrogen bromide the 2-bromo-androstane-ol- (17) -one- (3) -acetate is heated for 6 hours to about 190 C. with sodium acetateor potassium acetate in a solution of glacial acetic acid. After dilution with water the reaction product is extracted with ether. .The

ethereal solution is washed with water until neutral, dried and evaporated. By recrystallizing the residue from hexane there is obtained A androstene-ol-(l'l)-one-(3)-acetate of the formula I OH: CH: H

. l o.co.c11= C By alkaline saponiflcation of the unsaturated ester the corresponding alcohol is obtained. The latter is also obtainable directly by starting from the free alcohol instead of from the ester.

It is also possible to start from another ester or an ether of the androstane-ol-(1'D-one-(3).

Example 3 3.04 grams of the ll-methyl-androstane-ol- (17) -one-'(3) of the formula or melting point 192 C. obtained as described n French Patent No. 815,896 are mixed in glacial acetic acid solution with 1.6 grams of bromine. The2-bromo-17 -methyl-androstane-ol-(1'7) -one- (3) thus obtained is purified in the manner adopted in the preceding examples and then heated with dimethylaniline or potassium acetate in glacial acetic acid unc er pressure to eliminate hydrogen bromide, whereby the A -17- methyl-androstene-ol-(l'l) -o ne-(3) of the formula OH: on.

is obtained. I

The reaction may be carried out in analogous Example 4 2.9 grams of aetio-cholane-ol-(l'l) -one-(3) of the formula CH: CH:

are dissolved in 60 cc. of glacial acetic acid, and

' after addition of a few drops of a solution of hydrogen bromide in glacial acetic acid, the solution is gradually mixed with one of 1.6 grams of bromine in 10 cc. of glacial acetic acid. Decolorizatlon occurs at once. cipitated by addition of water and then recrystallized from dilute acetone; it is thus obtained in the form of splendid needles. For the purpose of eliminating hydrogen bromide the 4-bromo-androstane-ol-(17)-one-(3) is heated with pyridine for 2 hours to about C. After dilution with much water the reaction product is extracted with ether. The ethereal solution is washed repeatedly with dilute sulfuric acid, sodium. bicarbonate solution and finally with water until neutral, dried and evaporated. By recrystallizing the residue from hexane or isopropyl ether, the A androstene-ol-(l'l) -one-(3) of the formula other tertiary bases, such as quinoline or dimethylaniline or salts of organic acids, such-as the alkali salts or alkaline earth salts of acetic acid, propionic acid or benzoic acid. Further it is possible to start from a derivative of aetio-cholaneol-(17)-one-(3), such as an ester or ether, in-

stead of from aetlo-ch01ane-ol-(17)-one-(3) itself. For the halogenation of the oxy-ketone there may also be used for instance chlorine.

What we claim is: 1. A process for the manufacture of a-p-unsaturated 3-ketones of the cyclopentanohydrophe- 'nanthrene series, comprising causing halogen to act on saturated 3-keto-cyclopentanohydrophe- The product is pre-' nanthrenes containing in the l'l-position .a member of the group consisting of wherein R1 is a member of the group consisting of free hydroxyl, esterifled hydroxyl and etherified hydroxyl, and R2 is a member of the group consisting of alkyl and hydrogen, and,

treating the halogen compounds thus produced with an agent that eliminates hydrogen halide. v

2. A process for the manufacture of unsaturated A -ketones of the cyclopentanohydrophenanthrene series of the formula CH; CH:

wherein R1 means acyl and R: is a member of the group consisting of alkyl and hydrogen, and

comprising causing halogen to act on aetiocholane-dione- (3,17) of the formula CH CH and treating the halogen compound thus produced with an agent that eliminates hydrogen halide.

5. A process for the manufacture of unsaturated A -3-ketones of the cyclopentanohydrophenanthrene series of the formula treating the halogencompounds thus produced with an agent that eliminates hydrogen halide.

3. A process for the manufacture of A androstene-ol-(l'l)-one-(3)-acetate of the formula CH1 OH;

comprising causing halogen to act on androstene- '01-(17) -one-(3) -acetate of the formula CH: CH8 H and treating the halogen compound thus produced with an agent that eliminates hydrogen halide.

4. A process for the manufacture of 11 androstene-dione-(3,17) of the formul CH; CH:

CH: CH: R

i LD

wherein R1 is a member of the group consisting of acyl and hydrogen and R1 is a member of the group consisting of alkyl and hydrogen, comprising causing halogen to act on 3-keto-aetiocholanes of the formula CH1 CHI I OR| wherein R1 is a member of the group consisting of acyl and hydrogen and R2 is a member of the group consisting of alkyl and hydrogen, and treats ing the halogen compounds thus produced with an agent that eliminates hydrogen halide.

6. A process for the manufacture of A androstene-o1-(17)-one-(3) of the formula CH: OH: H

comprising causing halogen to act on aetiocholane ol-(17) -one-(3) of the formula and treating the halogen compound thus produfied with an agent that eliminates hydrogen ha de.

4 -2,2eo,aas

7. The zi -androstene-ol-(in -one- (3) -acetate or the formula v V a V CB: -o.co-cm 8; Amethod for the production of 3-ketones oi the cyclopentano-10,13-'-dimethyl polyhydro phenanthrenes which are unsaturated in the first ring. "comprising reacting a saturated 3-keto-17- 15 Recyclopentano-10,13-dimethyl polyhydro phenanthrene compound, wherein R is a member of the group consistingot ing oi the hydroxyl group and groups which with the aid of hydrolysis can be replaced by a hy-;

droiry group, and x analiwl radical, with a halo- 25 gen to introduce halogen into the first ring, and then" reacting the halogenated compound with an agent capable of splitting oi! hydrogen halide thereirom. v

and =0; B being a member of the class consist:

9. A"method for the. production 0! 3-ketones oi the cyclopentano-lfidii-dimethyl polyhydro phenanthrenes which are unsaturated in the first ring, comprising reacting androstandione with a halogen to introduce halogen into the first ring. and then reacting the halogenated compound with an agent capable oisplitting 03 hydrogen halide therefrom. 4

10. A method tor the*production ct 3-ketones of the cyclopentano-lmlti-dimethyl polwhydro phenanthrenes which are unsaturated-in the first ring, comprising reacting an androstanol-l'l-onefrom.. ALBERT 

